This invention relates to hydroxamic acid derivatives, and to their use in medicine.
Metalloproteinases, including matrix metalloproteinase (MMP), collagenase, gelatinase and TNFxcex1 convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the ADAM or ADAM-TS families. Members of the ADAM family include TNFxcex1 convertase (TACE) and ADAM-10, which can cause the release of TNFxcex1 from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and are also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
The invention encompasses novel compounds of formula (I) which are inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases mediated by those enzymes, including degenerative diseases and certain cancers.
Novel compounds according to a first aspect of the invention are represented by formula (I): 
wherein
R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W and WR4);
R3 is a hydrogen atom or an alkyl group;
or R2, R3 and the carbon atom to which they are attached together represent a carbocylic or heterocyclic ring (either of which may be substituted with one or more substituents chosen from R4, W or WR4);
A is a heterocylic ring (attached to SO2 through a nitrogen atom) optionally substituted with R4;
B is an aryl or heteroaryl ring, optionally substituted with one or more R5;
D is an aryl or heteroaryl ring, optionally substituted with one or more R5; or a heterocyclic ring (attached through a carbon atom) optionally substituted with R4 at any available carbon atom or with R14 at any available nitrogen atom;
provided that both B and D are both not phenyl;
R4 is OR6, COR10, CO2R9, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, CN, xe2x95x90O or xe2x95x90NOR10, provided that R4 is not xe2x95x90O or xe2x95x90NOR10 if a substituent on an aromatic ring;
R5 is alkyl, cycloalkyl, CF3, OR6, COR10, S(O)qR10, CO2R9, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN;
R6 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R7 and R8, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
R9 is H, alkyl or cycloalkyl;
R10 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R11 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR12, CONR7R8, S(O)qR12 or S(O)qNR7R8, or R10 and R11 and the nitrogen to which they are attached together represent a heterocyclic ring optionally substituted by R13;
R12 is OR6 or R13;
R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl;
R14 is a hydrogen atom, alkyl or cycloalkyl;
q is 0, 1 or 2;
W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl and
X is xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, S(O)qxe2x80x94, xe2x80x94N(R10)xe2x80x94, or is absent;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.